Adjuvants for rectal delivery of drug substances

ABSTRACT

A method and drug form for enhancing the rate of absorption of a rectally administered drug from the rectal compartment into the blood stream of a warm blooded animal. The method includes the steps of preparing a β-lactam drug form capable of being rectally administered. The drug form comprises a therapeutically effective unit dosage amount of a selected drug of the type which is capable of being absorbed into the blood stream from the rectal compartment and hydroxy aryl or hydroxy aralkyl acids or salts, amides or esters thereof, the hydroxy aryl or hydroxy aralkyl acids or salts, amides or esters thereof being present in the drug form in a sufficient amount to be effective in enhancing the drug absorption rate, when rectally administering the drug form to warm blooded animals.

REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part application of our co-pendingapplication Ser. No. 213,121, filed Dec. 5, 1980, abandoned, which is acontinuation-in-part application of Ser. No. 105,645 filed Dec. 20,1979, and now abandoned.

BACKGROUND OF THE INVENTION Field of the Invention and Description ofthe Prior Art

This invention relates to a method for administering drugs to warmblooded animals by rectal delivery and it particularly relates to amethod for enhancing the rate of absorption of such rectally delivereddrugs from the rectal compartment to the blood stream; this inventionalso relates to improved rectal suppository drug forms used in thepractice of such method.

One known method of drug administration is accomplished by theincorporation of a drug in a "suppository", which generally speaking, isa medicated solid dosage form generally intended for use in the rectum,vagina, and to a lesser extent, in the urethra. Molded rectalsuppositories usually employ vehicles that melt or soften at bodytemperatures so that the drug may be released for use. On the otherhand, soft elastic gelatin capsule suppositories rely on the presence ofmoisture in the rectum which causes the capsule to open and release itsliquid contents which contains its therapeutic agent. Drugs administeredin suppository form are administered for either local or systemiceffect. The action of the drug is dependent on the nature of the drug,its concentration, and its rate of absorption. Although rectalsuppositories are commonly used for the treatment of constipation andhemorrhoids, that is, for local effect, such rectal suppositories arealso administered rectally for systemic action. A wide variety of drugsmay be rectally administered, as by the use of suppositories, including,for example, analgesics, antispasmodics, sedatives, tranquilizers, andantibacterial agents.

Rectal drug administration has many advantages over other routes of drugadministration, such as oral administration and parenteraladministration. For example, many drug substances that are given orallyundergo inactivation in the stomach because of the acidic, enzymaticcontent of the stomach or the drug may be subject to digestive attack inthe gut and/or to microbial degradation in the lower gut. Oraladministration of drugs also directs all of the absorbed substancesthrough the liver where they can be inactivated or reduced ineffectiveness.

Rectal administration overcomes wholly, or in part, these knowndisadvantages of oral drug administration. Rectal drug administrationalso has advantages over parenteral administration. For example, rectaldrug administration does not require highly trained personnel requiredfor parenteral administration and also represents significantly lesshazard to te patient.

In view of the known disadvantages or oral and parenteral drugadministration, drug administration by rectal delivery enables manydrugs to be absorbed from the anorectal area, and yet retain theirtherapeutic value. The lower hemorrhoidal vein, surrounding the colonand rectum, enters the inferior vena cava and thereby bypasses theliver. Therefore, drugs are absorbed directly into the generalcirculation when rectally administered. For further background on rectaldelivery of drugs, reference is made herein to an article entitled"Rectal Administration of Drugs" by N. Senior, "Advances inPharmaceutical Sciences", edited by Bean, Beckett, and Corlass, VolumeIV, Academic Press (1974) and to Chapter 8, "Suppositories", by JoachimAnschel and Herbert A. Lieberman, Lachman and Lieberman "Theory andPractice of Industrial Pharmacy", Lea and Febiger (1976).

Despite the known advantages of rectal administration of drugs, therectal administration of drugs is not totally without problems. First,many rectally administered drugs are poorly absorbed while others areslowly absorbed and, if so, are often inactivated or degraded whilestill in the rectal compartment. It would therefore be highlyadvantageous if rectally administered drug substances could have theirrate of absorption from the rectal compartment to the blood streamenhanced.

SUMMARY OF THE INVENTION

It is therefore an important object of the present invention to providea unique method for enhancing the absorption rate of rectallyadministered drugs from the rectal compartment to the blood stream.

It is also an object of the present invention to provide an improvedrectal suppository drug form which enhances the absorption rate ofrectally delivered drugs contained in a soft elastic gelatin capsule ora molded suppository.

It is a further important object of the present invention to provide animproved method for administering drugs by the use of rectalsuppositories wherein enhanced absorption results from the incorporationof hydroxy aryl or hydroxy aralkyl acids or salts, amides or estersthereof into the drug formulation.

It is yet another important object of this invention to provide animproved rectal suppository having an enhanced absorption rate of aselected drug therefrom when in the rectal compartment, wherein hydroxyaryl or hydroxy aralkyl acids or salts, amides or esters thereof areincorporated into a drug formulation contained within a soft elasticgelatin capsule or molded type of rectal suppository.

Further purposes and objects of this invention will appear as thespecification proceeds.

The foregoing objects are accomplished by providing a method andsuppository drug form wherein the absorption rate of rectallyadministered drugs into the bloodstream of warm blooded animals isenhanced, the method comprising the steps of preparing a drug formcapable of being rectally administered, the drug form comprising aneffective unit dosage amount of a drug of a type which is capable ofbeing absorbed from the rectal compartment into the blood stream andhydroxy aryl or hydroxy aralkyl acids or salts, amides or estersthereof, the hydroxy aryl or hyroxy aralkyl acids or salts, amides oresters thereof being present in said drug form in an amount sufficientto be effective in enhancing the absorption rate of a drug into theblood stream from the rectal compartment, and thereafter rectallyadministering the drug form to a warm blooded animal.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention, generally, comprises the steps of preparing adrug form capable of being rectally administered, wherein the drug formcomprises an effective unit dosage amount of a drug capable of beingabsorbed into the blood stream of a warm blooded animal from the rectalcompartment and hyroxy aryl or hydroxy aralkyl acids or salts, amides oresters thereof, the hydroxy aryl or hydroxy aralkyl acids or salts,amides or esters thereof being present in the drug form in a sufficientamount to be effective in enhancing the absorption rate, and rectallyadministering the drug form to the warm blooded animal.

Our method for enhancing the rate of absorption of drugs from the rectalcompartment is useful for a wide range of drugs or drug categoriesincluding, β-lactam antibiotics such as penicillin, including penicillinG., penicillin V., ampicillin, amoxicillin, methacillin, carbenicillin,ticaricillin and cephalosporins, such as cephalosporin C, cefazolin,cefoxitin, cephamandole, cefuroxine, cephaprin, cephaloridine,cephmetazole, cepheperin, cephanone, oxacephalosporin, S-6059, andT-1551 all of which drugs are capable of being absorbed into the bloodstream of a patient from the rectal compartment. Other specific drugsuseful in the method and in combination with the hereinafter describedadjuvants will be hereinafter identified. The amount of the drug used inour method for enhancing drug absorption varies over a wide range,generally any therapeutically effective unit dosage amount of theselected drug is used.

The hydroxy aryl or hydroxy aralkyl acids or salts, amides or estersthereof, that are used as the adjuvants in our method and in oursuppositories, have the following structural formulae including thevarious isomers possible within the formulae set forth: ##STR1## whereinR₁ is a radical selected from --CO₂ H, --(CH₂)_(n) --COOH, ##STR2##--SO₃ H, --CH₂ SO₃ H, X(CH₂)_(n) CO₂ H, SO₂ NHR₄, PO(OH)N(OH)₂,PO(OH)OR₄, or a pharmaceutically acceptable salt thereof

wherein R₂ is a radical selected from OH, H a lower alkoxy radicalhaving 1-10 carbon atoms, a lower alkyl radical having 1-10 carbonatoms, a lower alkenyl radical having 2-5 carbon atoms, a lower alkanoylradical having 1-5 carbon atoms, a carboxy radical, a carbo-lower alkoxyradical having 1-5 carbon atoms, a halo radical, a mono-, di-, ortri-halo lower alkyl radical having 1-5 carbon atoms, an amino radical,a mono- or di-lower alkyl amino radical having 1-5 carbon atoms, acarbamyl radical, a lower mono- or di-alkyl carbamyl radical wherein thealkyl group has 1-5 carbon atoms, a thio radical, a lower alkyl thioradical wherein the alkyl group has 1-5 carbon atoms, a cyano radical, alower alkyl sulfone radical wherein the alkyl group has 1-5 carbonatoms, a lower alkyl sulfoxide radical wherein the alkyl group has 1-5carbon atoms, a nitro radical, N(CN₂)₂, C(CN)₃, an alkynyl radicalhaving 2-6 carbon atoms, a cycloalkyl radical having 3-10 carbon atoms,a cycloalkenyl radical having 3-10 carbon atoms, an aryl radicalincluding phenyl, a hetroaryl radical including thiophenyl andimadazoalyl, or a heterocycloalkyl radical including morphilinyl andpiperdinyl,

wherein R₃ is a straight or branched alkyl radical having 1-6 carbonatoms or a hdroxy radical,

wherein R₄ is H or a lower alkyl radical having 1-5 carbon atoms,

wherein X is O or S,

wherein n is an integer of 0-5,

wherein y is 1 or 2, and

when y is 2, both the R₂ radicals, taken together, can form a ringcontaining O, N or S.

More preferred adjuvants are those having the formula: ##STR3## whereinR₁ is a radical selected from --CO₂ H, --(CH₂)--COOH, --CH═CH--CO₂ H,##STR4## --SO₃ H, --CH₂ SO₃ H, or O(CH₂) CO₂ H or a pharmaceuticallyacceptable salt thereof wherein R₂ is selected from OH, H, a loweralkoxy radical having 1-10 carbon atoms, a lower alkyl radical hving1-10 carbon atoms, a halo radical, a mono-, di-, or tri-halo lower alkylradical wherein the alkyl group has 1-5 carbon atoms, a lower alkyl thioradical wherein the alkyl radical has 1-5 carbon atoms, a cycloalkylradical having 3-10 carbon atoms, or a cycloalkenyl radical having 3-10carbon atoms and wherein y is an integer of 1 or 2.

Highly preferred adjuvants are those having the formula: ##STR5##wherein R1 is CO₂ H, --(CH₂)--COOH, ##STR6## or SO₃ H, or apharmaceutically acceptable salt thereof wherein R₂ is OH, H, a loweralkoxy radical, including methoxy, ethoxy, butoxy, or octyloxy, a loweralkyl radical including methyl, isopropyl, ethyl, t-butyl, n-butyl, ort-octyl, a halo radical, or a tri-halo lower alkyl radical includingtrifluoromethyl, and wherein y is an integer of 1 or 2.

Specific adjuvants useful in our method and drug forms includesalicyclic acid; 5-methoxy salicylic acid; 3,4-dihydroxyphenylaceticacid, (DOPAC); and homovanillic acid; as well as the sodium saltsthereof.

As in the case of the drugs used in our method and suppositories, theamount of adjuvant used may vary over a wide range; in general, theidentity and the amount of the adjuvant used in connection with the drugare selected in order to be effective in enhancing the absorption rateof the drug from the rectal compartment into the bloodstream.

Generally the amount of adjuvant in our drug forms (suppositories) isfrom 100-1000 mg in each unit dose. The percentage of adjuvant in thetotal combination of drug plus adjuvant is 20-95% with a preferred ratioof adjuvant in the total combination of adjuvant plus drug being 30-60%.A most preferred ratio of adjuvant to adjuvant plus drug is 50%.

The particular method used for the rectal administration of the drug andthe adjuvant is preferably by use of the appropriate size, shape or formof any of the various types of rectal suppositories known to thepharmaceutical art; alternatively, the drug may be administered with theadjuvant by means of microenema. Useful rectal suppositories with whichthe present method may be used include cocoa butter suppositories,synthetic fat suppositories, and gelatin capsules including soft elasticgelatin capsule type suppositories as well as other controlled releasedevices such as an osmotic pump or other polymeric devices.

A preferred form of suppository comprises a soft elastic gelatin capsulehaving an outer shell which encloses the drug and the adjuvant in asuitable vehicle which will not attack the walls of the seamless gelatincapsule. The shell encapsulates a preselected drug form and theadjuvant. The gelatin capsule shell may be formulated in accordance withconventional techniques for making filled, seamless, soft elasticgelatin capsules containing therapeutically effective unit dosageamounts of the active drug ingredient. For example, one conventionalshell formulation includes about 30-53 parts by weight of gelatin, 15-48parts by weight of a plasticizer, such as glycerine or sorbitol, andabout 16-40 parts by weight of water. Additionally, the gelatin shellmay contain preservatives such as mixed parabens, ordinarily methyl orpropyl parabens in about a 4:1 ratio. The parabens may be incorporatedin the shell formulation in minor proportions as compared to the totalweight of the shell formulation. Conventional gelatin capsules utilizegelatin having a bloom value of about 160-200 although this amount maybe varied.

In a conventional manner, the gelatin composition is mixed and meltedunder vacuum conditions. The capsules may be simultaneously formed andfilled using a conventional method and apparatus such as disclosed, forexample, in U.S. Pat. Nos. 1,970,396; 2,288,327; and 2,318,718. Thegelatin capsules are formed into a desired shape and size for insertioninto the rectal compartment. It is to be understood, however, that theparticular method used for making the soft elastic gelatin shell and forincorporating the fill therein are not considered part of the inventionherein.

One of the more important uses of our method and suppository for rectaladministration of drugs is in the administration of sustained release orprogrammed release drug forms which will slowly release the drugsubstances into the rectal compartment of a warm blooded animal. Thepresent method and suppository permit the rapid clearance of thereleased drug into the blood stream by way of the lower hemorrhoidalvein, instead of moving upwards into the lower gut. This techniquethereby reduces or avoids loss of drug effectiveness associated withpassage of the drug through the liver.

The following data sets forth specific experiments illustrating variousembodiments of the present invention.

EXAMPLE I

The effect of the salicylate type absorption adjuvants on the rectalabsorption of β-lactam antibiotics in the Beagle dog is presented in theaccompanying tables. The dog model is as previously described exceptthat the blood samples are assayed for antibiotic activity and/or drugconcentration using a microbiological assay and/or a high pressureliquid chromatographic technique. As a relative measure of rectal drugdelivery, data are presented as "bioavailability" where 1.00 isequivalent to i.v. administration of the target drug.

Referring to Table I, the effect of sodium 5-methoxysalicylate, sodiumsalicylate, and sodium homovanillate on the rectal absorption ofcefmetazole is shown. Clearly, these adjuvant compounds dramaticallyenhance the rectal absorption of cefmetazole compared to thoseformulations which contain no absorption adjuvant.

Referring to Table II, the effect of sodium 5-methoxysalicylate on therectal absorption of cefoxitin is presented. In this instance the bestformulation containing absorption adjuvant increased rectalbioavilability 13-fold.

Referring to Table III the effect of sodium 5-methoxysalicylate on therectal absorption of Penicillin G is demonstrated. In this instance, thebest formulation with adjuvant afforded total delivery of the drug,compared to a delivery of 4% for the same formulation without absorptionadjuvant.

                                      TABLE I                                     __________________________________________________________________________    Relative bioavailability* of sodium cefmetazole after rectal                  administration compared with intravenous administration with                  various absorption adjuvants (Beagle dog model).                              Dose of    Sodium                                                             Adjuvant   5-methoxy-                                                                            sodium sodium                                              (mg/body)  salicylate                                                                            salicylate                                                                           homovanillate                                       __________________________________________________________________________    Rx I                                                                              (150 mg of sodium cefmetazole) + (adjuvant) + (Witepsol H-15) = 1 g       200        --      0.90 ± 0.13                                                                       0.90 ± 0.11                                                                          (n = 2)                                   150        0.94 ± 0.20                                                                        0.82 ± 0.20                                                                       0.73 ± 0.15                                                                          (n = 4)                                   100        0.92 ± 0.16                                                                        0.56 ± 0.21                                                                       0.59 ± 0.24                                                                          (n = 2)                                    75        0.30 ± 0.05                                                                        0.34 ± 0.10                                                                       0.35 ± 0.09                                                                          (n = 4)                                    0         0.05    0.05   0.05      (n = 3)                                   Rx II                                                                             (150 mg of the free acid of cefmetazole) + (adjuvant) + (Witepsol             H-15) = 1 g                                                               150        0.69 ± 0.21                                                                        0.69 ± 0.25                                                                       0.50 ± 0.21                                                                          (n = 4)                                   100        0.63 ± 0.26                                                                        0.44 ± 0.20                                                                       0.40 ± 0.12                                                                          (n = 2)                                    0         0.05    0.05   0.05      (n = 2)                                   Rx III                                                                            (150 mg of sodium cefmetazole) + (adjuvant) + (phosphate buffer) = 1          mL                                                                        300        0.37 ± 0.09                                                                        0.30 ± 0.07                                                                       --        (n = 4)                                   150        0.18 ± 0.04                                                                        0.14 ± 0.04                                                                       --        (n = 4)                                    0         0.02    0.02                                                       __________________________________________________________________________     ##STR7##                                                                      BA ± SD                                                               

                                      TABLE II                                    __________________________________________________________________________    Rectal Bioavailability of Cefoxitin                                                                         Rectal                                                                        Bioavailability                                                                         Rectal                                                Dose of       with adjuvant                                                                           Bioavailability                       Dosage     Dose of                                                                            5-methoxy     relative to without                                                                     relative to IV                        form       Cefoxitin                                                                          salicylate                                                                          [AUC]*  [AUG].sub.p (dose).sub.a                                                                [AUC].sub.r (dose).sub.iv             and base   mg/body                                                                            mg/body                                                                             mg min/mL                                                                             [AUC].sub.a (dose).sub.p                                                                [AUC].sub.iv (dose).sub.r                                                             n                             __________________________________________________________________________    i.v.-      50   --    1074 ± 111             4                             injection                                                                     rectal administration-                                                        suppository-                                                                             150  --    82 ± 30        0.05    4                             Witepsol H-15                                                                            75    50   587 ± 233**                                                                        14        0.36    4                                        75    75   828 ± 231**                                                                        20        0.51    4                                        75   100   1050 ± 250**                                                                       26        0.65    4                             microenema-                                                                              75   100   481 ± 123**                                                                        12        0.30    4                             gelatin gel                                                                              75   200   1242 + 192**                                                                          30        0.77    4                             buffer solution                                                                          75   150   189 ± 52**                                                                          5        0.12    4                             __________________________________________________________________________     *[AUC] = [AUC].sub.0 min..sup.120 min.                                        **p 0.001 versus rectal administration in absence of adjuvant.                Subscripts:                                                                   .sub.r = rectal administration,                                               .sub.iv = IV administration,                                                  .sub.p = adjuvant present,                                                    .sub.a = adjuvant absent                                                 

                                      TABLE III                                   __________________________________________________________________________    Rectal Bioavailability of Penicillin G                                                                       Rectal                                                                        Bioavailability                                                                         Rectal                                                 Dose of      with adjuvant                                                                           Bioavailability                      Dosage     Dose of                                                                              5-methoxy    relative to without                                                                     relative to IV                       form       Penicillin G                                                                         salicylate                                                                          [AUC]* [AUC].sub.p (dose).sub.a                                                                [AUC].sub.r (dose).sub.iv            and base   mg/body                                                                              mg/body                                                                             mg min/mL                                                                            [AUC].sub.a (dose).sub.p                                                                [AUC].sub.iv (dose).sub.r                                                             n                            __________________________________________________________________________    i.v.-      50     --    288 ± 46              4                            injection                                                                     rectal administration-                                                        suppository-                                                                             150    --    38 ± 3        0.04    4                            Witepsol H-15                                                                            75      50   178 ± 19**                                                                         9        0.41    4                                       75      75   249 ± 64**                                                                        13        0.58    4                                       75     100    450 ± 208**                                                                      24        1.04    8                            microenema-                                                                              75     100   160 ± 56**                                                                         8        0.37    8                            gelatin gel                                                                              75     150   301 ± 73**                                                                        16        0.70    4                            buffer solution                                                                          75     150   149 ± 29**                                                                         8        0.35    4                            __________________________________________________________________________     *[AUC] = [AUC].sub.0 min..sup.120 min.                                        **p 0.001 versus rectal administration in absence of adjuvant, ttest.         Subscripts:                                                                   .sub.r = rectal administration,                                               .sub.iv = IV administration,                                                  .sub.p = adjuvant present,                                                    .sub.a = adjuvant absent                                                 

EXAMPLE II

The ability of various of the adjuvants of the present invention toenhance the rate of absorption of significant drugs which are rectallyadministered, from the rectal compartment into the blood stream, isdemonstrated with an in situ perfusion method of the rectum. The rectumof a male Sprague-Dowley rat weighing 275-300 g., is exposed by anabdominal incision, a glass cannula is inserted into the distaldirection and tied firmly to keep it in position. A second cannula isinserted through the anus 1 cm. inside the rectum and secured byligation. Thus, about 2 cm. of the rectum is exposed to the perfusate.The perfustate (6 ml.) is circulated at a rate of 2 ml./min. at 38° C.As perfustate, 1/15 M-phosphate buffer solutions are used and the ionicstrength of the perfusate is adjusted to 0.75 with sodiumchloride asnecessary. The adjuvant is employed at a concentration of 0.5%, whilethe concentration of the various drugs is varied in accordance with theknown effective dosages for said drugs. The amount of drug remaining inthe perfustate is analyzed as a function of time by appropriate methods,e.g., by high-pressure liquid chromatography. Blood levels are alsomeasured in blood samples taken from a vein in the leg of the rat. Theresults of this method show that the percent absorption of the variousdrugs after 1 hour from the perfusate in the rat rectum issignificantlty enhanced by the presence of an adjuvant of the presentinvention.

Following is a table of drug and adjuvant combinations which areevaluated in accordance with the method described above:

    ______________________________________                                        Drug                  Adjuvant                                                ______________________________________                                        1.   Ampicillin           sodium salicylate                                   2.   Amoxicillin          sodium homovanillate                                3.   Methacillin          2,5-dihydroxy                                                                 benzoate                                            4.   Cephaprin            sodium 5-methoxy                                                              salicylate                                          5.   Cephanone            sodium 3-methoxy                                                              salicylate                                          6.   (6R-cis)-3-[ [(Aminocarbonyl                                                                       sodium salicylate                                        oxy]methyl]-7-methoxy-8-                                                      oxo-7-[(2-thienylacetyl))                                                     amino]-5-thia-1-azabicyclo-                                                   [4.2.0]oct-2-ene-2-carboxylic                                                 acid (cefoxitin);                                                        7.   Carbenicillin        2,5-dihydroxy                                                                 benzoate                                            8.   Penicillin G         sodium homovanillate                                9.   Ticaricillin         sodium salicylate                                   10.  Cefazolin            sodium 5-methoxy                                                              salicylate                                          11.  Cepheperin           sodium salicylate                                   12.  Cephaloridine        sodium salicylate                                   13.  Cephalosporic C      sodium homovanillate                                14.  Cephmetazole         sodium 5-methoxy                                                              salicylate                                          15.  Oxacephalosporin     sodium 3-methoxy                                                              salicylate                                          16.  Penicillin V         sodium salicylate                                   17.  N--formimidoyl thienamycin                                                                         2,5-dihydroxy                                            monohydrate          benzoate                                            18.  Cefuroxine           sodium homovanillate                                19.  Carbenicillin        sodium homovanillate                                20.  Cefazolin            sodium salicylate                                   21.  Amoxicillin          sodium 5-methoxy                                                              salicylate                                          22.  Ampicillin           sodium salicylate                                   23.  Carbenicillin        sodium salicylate                                   24.  Cephaprin            sodium homovanillate                                25.  Oxacephalosporin     2,5-dihydroxy                                                                 benzoate                                            26.  Ticaricillin         sodium 5-methoxy                                                              salicylate                                          27.  Carbenicillin        sodium 3-methoxy                                                              salicylate                                          28.  Penicillin V         sodium salicylate                                   29.  Penicillin G         2,5-dihydroxy                                                                 benzoate                                            30.  7-[(hydroxyphenylacetyl)amino]-                                                                    sodium homovanillate                                     3-[[(1-methyl-1H--tetrazol-5-yl)-                                             thio] methyul]-8-oxo-5-thia-1-                                                azabicyclo[4.2.0]oct-2-ene-2-                                                 carboxylic acid (cephamandole)                                           31.  Methacillin          sodium homovanillate                                32.  6-[[amino(4-hydroxyphenyl)acetyl]-                                                                 sodium salicylate                                        amino]-3,3-dimethyl--7-oxo-4-thia-                                            1-azabicyclo-[3.2.0]heptane-2-                                                carboxylic acid (amoxicillin)                                            33.  Ticaricillin         sodium 5-methoxy                                                              salicylate                                          34.  Cefuroxine           sodium salicylate                                   35.  Cephamandole         sodium salicylate                                   ______________________________________                                    

As already described, the method of the present invention for enhancingthe rate of absorption of drugs from the rectal compartment is usefulfor a wide range of drugs. Without limiting the broad applicability ofthe novel method, there is also pointed out below a number of drugs forwhich the novel method is particularly useful, thus comprising preferredembodiments of the present invention:

(6R-cis)-3-[[Aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (cefoxitin);

N-formimidoyl thienamycin monohydrate

7-[(hydroxyphenylacetyl)amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (cephamandole)

6-[[amino(4-hydroxyphenyl)acetyl]-amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid (amoxicillin)

EXAMPLE III

A suppository suitable for human use is preferred using the followingingredients:

    ______________________________________                                        Ingredient              Amount                                                ______________________________________                                        A.     Sodium 5-methoxy       500    mg.                                             salicylate                                                             B.     Cefoxitin              1      g.                                       C.     Witepsol ® H-15    1.5    g.                                              suppository excipient.sup.1                                                   [glycerol esters of mixtures of                                               saturated vegetable fatty acids,                                              predominantly lauric acid, derived                                            from purified, specially selected                                             coconut palm kernels, by separation                                           into fatty acid and glyceride                                                 portions, fractional distillation                                             of the fatty acid portion,                                                    followed by hydrogenation and                                                 esterification with glycerin.]                                         ______________________________________                                    

Dry ingredients A and B are ground together to form a well-mixed, finepowder. Separately, ingredient C is heated to 40°-50° C. till fluid,after which it is mixed with the fine powder mixture of A and B andpoured into a mold to form a unit dosage suppository.

In like manner, the following amounts of various drugs may beincorporated into supositories using the same excipient and adjuvant andpreparation technique described above:

    ______________________________________                                        Drug                Amount                                                    ______________________________________                                        penicillin G        275 mg.                                                   amoxicillin         200 mg.                                                   cephaprin           250 mg.                                                   cephanone           250 mg.                                                   cephalosporin C     275 mg.                                                   ampicillin          500 mg.                                                   carbenicillin       200 mg.                                                   ticaricillin        250 mg.                                                   cefuroxine          250 mg.                                                   cephaloridine       200 mg.                                                   oxacephalosporin    200 mg.                                                   cephaprin           225 mg.                                                   cepheperin          225 mg.                                                   cefazolin           200 mg.                                                   cephamandole        1000 mg.                                                  amoxicillin         500 mg.                                                   N--formimidoyl thienamycin                                                                        500 mg.                                                   monohydrate                                                                   ______________________________________                                    

The adjuvants may be chosen from the following salts or their acids.

Sodium 5-methoxysalicylate

Sodium salicylate

Sodium homovanilate

Sodium 2,5-dihydroxybenzoate

Sodium 2,4-dihydroxybenzoate

Sodium 3,4-dihydroxymandelate

Sodium 3-methoxy-4-hydroxymandelate

Sodium 3-methoxy-4-hydroxycinnamate

Sodium 5-methoxy-2-hydroxyphenylsulfonate

Sodium 3-methylsalicylate

Sodium 5-methylsalicylate

Sodium 5-tert-octylsalicylate

Sodium 3-tert-butyl-6-methylsalicylate

Sodium 3,5-diisopropylsalicylate

Sodium 3-tert-butyl-5-methylsalicylate

Sodium quaicolsulfonate

Sodium 5-bromosalicylate

Sodium 3,5-dibromosalicylate

Sodium 5-iodosalicylate

Sodium 3,5-dibromosalicylate

Sodium 2-hydroxyphenylacetate

Sodium 3-hydroxy-2-naphthoate

Sodium mandelate

Sodium phenyllactate

Sodium 2-hydroxyphenylmethanesulfonate

Sodium 5-trifluoromethyl-2-hydroxybenzoate

Sodium 4-hydroxy-3-hydroxyphenylmethanesulfonate

Sodium 3-methoxysalicyalte

Sodium 5-octyloxysalicylate

Sodium 5-butoxysalicylate

Sodium p-hydroxyphenoxyacetate

Sodium 3,4-dihydroxyphenylacetate

Sodium 5-chlorosalicylate

Sodium 3,4-dihdyroxycinnamate

Sodium 3,5-dihydroxybenzoate

Sodium 2-hydroxy-3-methoxybenzoate

Sodium 1-hydroxy-2-naphthoate

Sodium salicylurate

EXAMPLE IV

The ability of various of the adjuvants of the present invention toenhance the rate of absorption of significant drugs which are rectallyadministered, from the rectal compartment into the blood stream, isdemonstrated with an in situ perfusion method of the rectum. The rectumof a male Sprague-Dawley rat weighing 275-300 g., is exposed by anabdominal incision, a glass cannula is inserted in the distal directionand tied firmly to keep it in position. A second cannula is insertedthrough the anus 1 cm. inside the rectam and secured by ligation. Thus,about 2 cm. of the rectum is exposed to the perfusate. The perfusate (6ml.) is circulated at a rate of 2 ml./min. at 38° C. As perfusate, 1/15M-phosphate buffer solutions are used and the ionic strength of theperfusate is adjusted to 0.75 with sodium chloride as necessary. Thehydroxyaromatic acid adjuvant is employed at a concentration of 0.5%,while the concentration of the various drugs is varied in accordancewith the known effective dosages for said drugs. The amount of drugremaining in the perfusate is analyzed as a function of time byappropriate methods, e.g. by high-pressure liquid chromatography. Bloodvessels are also measured by blood samples taken from a vein in the legof the rat. The results of this method show that the percent absorptionof the various drugs after 1 hour from the perfusate in the rat rectumis significantly enhanced by the presence of the adjuvant of the presentinvention. Following is a table of drug and adjuvant combinations whichare evaluated in accordance with the method described above:

    ______________________________________                                        1.     cephalosporin C  Sodium salicylate,                                           "                sodium benzoate,                                             "                sodium o-anisate,                                            "                sodium p-anisate,                                            "                sodium 3-methoxy                                             "                salicylate,                                                  "                sodium 2,4-dihydroxy                                         "                benzoate                                                     "                sodium 2,5-dihydroxy                                         "                benzoate,                                                    "                sodium 3,5-dihydroxy                                         "                benzoate                                                     "                sodium 2,4-dimethoxy                                         "                benzoate                                                     "                sodium homovanillate                                         "                sodium 5-methoxy                                             "                salicylate                                            2.     amoxicillin      Sodium salicylate,                                           "                sodium benzoate,                                             "                sodium o-anisate                                             "                sodium p-anisate,                                            "                sodium 3-methoxy                                             "                salicylate,                                                  "                sodium 2,4-dihydroxy                                         "                benzoate                                                     "                sodium 2,5-dihydroxy                                         "                benzoate,                                                    "                sodium 3,5-dihydroxy                                         "                benzoate                                                     "                sodium 2,4-dimethoxy                                         "                benzoate                                                     "                sodium homovanillate                                         "                sodium 5-methoxy                                             "                salicylate                                            3.     ampicillin       Sodium salicylate,                                           "                sodium benzoate,                                             "                                                                             "                sodium p-anisate,                                            "                sodium 3-methoxy                                             "                salicylate,                                                  "                sodium 2,4-dihydroxy                                         "                benzoate                                                     "                sodium 2,5-dihydroxy                                         "                benzoate,                                                    "                sodium 3,5-dihydroxy                                         "                benzoate                                                     "                sodium 2,4-dimethoxy                                         "                benzoate                                                     "                sodium homovanillate                                         "                sodium 5-methoxy                                             "                salicylate                                            4.     Cefoxitin        Sodium salicylate,                                           "                sodium benzoate,                                             "                sodium o-anisate                                             "                sodium p-anisate,                                            "                sodium 3-methoxy                                             "                salicylate,                                                  "                sodium 2,4-dihydroxy                                         "                benzoate                                                     "                sodium 2,5-dihydroxy                                         "                benzoate,                                                    "                sodium 3,5-dihydroxy                                         "                benzoate                                                     "                sodium 2,4-dimethoxy                                         "                benzoate                                                     "                sodium homovanillate                                         "                sodium 5-methoxy                                             "                salicylate                                            5.     Cefmetazole      Sodium salicylate,                                           "                sodium benzoate,                                             "                sodium o-anisate,                                            "                sodium p-anisate,                                            "                sodium 3-methoxy                                             "                salicylate,                                                  "                sodium 2,4-dihydroxy                                         "                benzoate                                                     "                sodium 2,5-dihydroxy                                         "                benzoate,                                                    "                sodium 3,5-dihydroxy                                         "                benzoate                                                     "                sodium 2,4-dimethoxy                                         "                benzoate                                                     "                sodium homovanillate                                         "                sodium 5-methoxy                                             "                salicylate                                            ______________________________________                                    

EXAMPLE V

The ability of various of the hydroxyaromatic acid adjuvants of thepresent invention to enhance the rate of absorption of significant drugswhich are rectally administered, from the rectal compartment into theblood stream, is also demonstrated with an in vivo absorption method ofthe rectum. The rectum of male Sprague-Dawley rat weighing 275-300 g.,is exposed by an abdominal incision. A 0.3 ml. sample of the drugsolution is injected into a 2 cm. section of the recum and the drugsolution is maintained in that section by ligating the rectum withthread. Alternatively, 0.3 ml. of the drug solution is injected into therectum using a cannula and the anus is tied firmly to prevent leakage ofthe drug solution. The hydroxyaromatic acid adjuvant is employed at aconcentration of 0.5%, while the concentration of the various drugs isvaried in accordance with the known effective dosages for said drugs.The amount of drug present in the blood is analyzed as a function oftime by extraction with ether at a pH of less than 2.0 afterdeproteinization with a 3% trichloroacetic acid solution. Followingcentrifugation, the ether layer is evaporated and the sediment isdissolved in methanol. This methanol sample containing the drug isassayed by high-pressure liquid chromatography. Blood levels are alsomeasured in blood samples taken from a vein in the leg of the rat usinga cannula.

The results of this method show that the percent absorption of thevarious drugs after one hour in the blood stream is significantlyenhanced by the presence of the hydroxyaromatic acid adjuvant of thepresent invention. Following is a table of drug and adjuvantcombinations which are evaluated in accordance with the method describedabove:

    ______________________________________                                        1.     penicillin G    Sodium salicylate,                                            "               sodium benzoate,                                              "               sodium o-anisate,                                             "               sodium p-anisate,                                             "               sodium 3-methoxy                                              "               salicylate,                                                   "               sodium 2,4-dihydroxy                                          "               benzoate                                                      "               sodium 2,5-dihydroxy                                          "               benzoate,                                                     "               sodium 3,5-dihydroxy                                          "               benzoate                                                      "               sodium 2,4-dimethoxy                                          "               benzoate                                                      "               sodium homovanillate                                          "               sodium 5-methoxy                                              "               salicylate                                             2.     carbenicillin   Sodium salicylate,                                            "               sodium benzoate,                                              "               sodium o-anisate                                              "               sodium p-anisate,                                             "               sodium 3-methoxy                                              "               salicylate,                                                   "               sodium 2,4-dihydroxy                                          "               benzoate                                                      "               sodium 2,5-dihydroxy                                          "               benzoate,                                                     "               sodium 3,5-dihydroxy                                          "               benzoate                                                      "               sodium 2,4-dimethoxy                                          "               benzoate                                                      "               sodium homovanillate                                          "               sodium 5-methoxy                                              "               salicylate                                             3.     methacillin     Sodium salicylate,                                            "               sodium benzoate,                                              "               sodium o-anisate,                                             "               sodium p-anisate,                                             "               sodium 3-methoxy                                              "               salicylate,                                                   "               sodium 2,4-dihydroxy                                          "               benzoate                                                      "               sodium 2,5-dihydroxy                                          "               benzoate,                                                     "               sodium 3,5-dihydroxy                                          "               benzoate                                                      "               sodium 2,4-dimethoxy                                          "               benzoate                                                      "               sodium homovanillate                                          "               sodium 5-methoxy                                              "               salicylate                                             4.     Cefmetazole     Sodium salicylate,                                            "               sodium benzoate,                                              "               sodium o-anisate,                                             "               sodium p-anisate,                                             "               sodium 3-methoxy                                              "               salicylate,                                                   "               sodium 2,4-dihydroxy                                          "               benzoate                                                      "               sodium 2,5-dihydroxy                                          "               benzoate,                                                     "               sodium 3,5-dihydroxy                                          "               benzoate                                                      "               sodium 2,4-dimethoxy                                          "               benzoate                                                      "               sodium homovanillate                                          "               sodium 5-methoxy                                              "               salicylate                                             ______________________________________                                    

EXAMPLE VI

The ability of various of the adjuvants of the present invention toenhance the rate of absorption of insulin which is rectallyadministered, from the rectal compartment into the blood stream, isdemonstrated with a microenema technique. Insulin is administered to amale Sprague-Dawley rat weighing 275°-300 g. using a microenema. Themicroenema is prepared with 0.2 M phosphate buffer, pH 5.0. A volume of0.3 ml. is delivered rectally. Blood samples are taken from a jugularvein of the rat at designated time intervals. The 0.3 ml. microenemaconsists of 5 mg. of adjuvant and 1.8 I.U. of insulin. Plasma levels ofglucose are measured using the ortho-toluidine method. The results ofthis method show that plasma glucose levels decrease rapidly afteradministration of the insulin microenema in the presence of adjuvant.The plasma glucose levels gradually recover from 60 to 120 minutes afteradministration. The adjuvant greatly enhanced the rectal absorption ofinsulin. The following is a table of drug and adjuvant combinationswhich are evaluated in accordance with the method described above:

    ______________________________________                                        Drug             Adjuvant                                                     ______________________________________                                        cephaprin        Sodium salicylate,                                           "                sodium 5-methoxy                                             "                salicylate,                                                  "                sodium 3-methoxy                                             "                salicylate,                                                  "                sodium homovanillate                                         ______________________________________                                    

EXAMPLE VII

The ability of various of the adjuvants of the present invention toenhance the rate of absorption of heparin which is rectallyadministered, from the rectal compartment into the blood stream, isdemonstrated using a microenema technique. A male Sprague-Dawley ratreceives 1000 units of heparin (Na salt) dissolved in a 0.1 ml aqueousmicroenema also containing 20 mg. of absorption adjuvant. The results ofthis method show that there is a dramatic increase in clotting timeafter rectal administration of heparin with adjuvant. Clotting timeswere greater than 90 minutes in blood samples taken at 15 minutesthrough 90 minutes. Following is a table of drug and adjuvantcombinations which are evaluated in accordance with the method describedabove:

    ______________________________________                                        Drug             Adjuvant                                                     ______________________________________                                        cefazolin        Sodium salicylate,                                           "                sodium 5-methoxy                                             "                salicylate,                                                  "                sodium 3-methoxy                                             "                salicylate,                                                  "                sodium homovanillate                                         ______________________________________                                    

EXAMPLE VIII

The ability of various of the adjuvants of the present invention toenhance the rate of absorption of cefmetazole which is rectallyadministered, from the rectal compartment into the blood stream, isdemonstrated using suppository and microenema formulations. Four malebeagle dogs weighing 9.5-11 kg. are used and are fasted for two daysprior to experimentation. Witepsol H-15 is used as an excipient toprepare the suppository formulation of cefmetazole. Microenemaformulations are prepared with aqueous 0.02 M phosphate buffer with afinal pH of 7.4. Either a 1 g. suppository or a 1 ml. microenema isgiven to each dog. The formulations may contain varying amounts ofadjuvant. Blood samples are taken from the foreleg vein at predeterminedsampling times after dosing. Blood samples are heparinized andcentrifuged at 3,000 rpm for 10 minutes. The concentration ofcefmetazole in the plasma of the dogs is analyzed as a function of timeusing plasma aliquots for the assay of cefmetazole. The results of thismethod show that the inclusion of adjuvant significantly enhanced therectal absorption of cefmetazole from both microenema and suppositoryformulations. The suppository formulations provide greaterbioavailabilty of cefmetazole than the microenema formulations ascompared with intravenous administration. Following is a table of drugsand adjuvant combinations which are evaluated in accordance with themethod described above:

    ______________________________________                                        Drug               Adjuvant                                                   ______________________________________                                        Sodium Cefmetazole Sodium salicylate,                                         "                  sodium 5-methoxy                                           "                  salicylate,                                                "                  sodium homovanillate                                       ______________________________________                                    

EXAMPLE IX

The ability of various of the adjuvants of the present invention toenhance the lymphatic transport of water soluble drugs after rectaladministration in conjunction with salicylate-based absorption adjuvantsis demonstrated with a microenema technique. A male Sprague-Dawley ratweighing 200-225 g. is anesthetized with pentobarbital and the thoracicduct is cannulated. Flow through this duct includes the mesentericdrainage. Drugs and absorption adjuvants are delivered in the form of a0.2 ml. aqueous microenema 1/15 M phosphate buffer, at a pH 7.4 (forinsulin a pH 5.0). Blood samples (0.3 ml) are taken from the externaljugular vein of the rat and centrifuged at 2000 rpm for ten minutes tocollect plasma. With the exception of phenol red, determination of drugconcentration in plasma and lymph is carried out using a high-pressureliquid chromatography technique at 254 nm. Plasma and lymph samples aredeproteinized with acetonitrile. Phenol red is determined at 540 nmafter adding 1.0 N sodium hydroxide to the plasma or lymphatic samples.Insulin is assayed with an immunospecific enzyme assay kit supplied byToyo Jozo Ltd., Japan. The results of this method show that theabsorption of the drug in plasma and in lymph collected from thethoracic duct is significantly enhanced by the presence of thehydroxyaromatic acid adjuvant of the present invention. Following is atable of drug and adjuvant combinations which are evaluated inaccordance with the method described above:

    ______________________________________                                        Drug                   Adjuvant                                               ______________________________________                                        1.     (6R--cis)-3-[[(Aminocarbonyl)                                                                     Sodium 5-methoxy                                          oxy]methyl]-7-methoxy-                                                                            salicylate,                                               8-oxo-7-[(2-thienylacetyl)                                                                        sodium salicylate                                         amino]-5-thia-1-azabicyclo                                                    [4.2.0]oct-2-ene-2-                                                           carboxylic acid (cefoxitin);                                           2.     cephalosporin C     Sodium 5-methoxy                                                              salicylate,                                                                   sodium salicylate                                  3.     penicillin G        Sodium 5-methoxy                                                              salicylate,                                                                   sodium salicylate                                  4.     methacillin         Sodium 5-methoxy                                                              salicylate,                                                                   sodium salicylate                                  ______________________________________                                    

EXAMPLE X

The ability of various of the dipeptide and metabolites of epinephrineadjuvants of the present invention to enhance the rate of absprption ofsignificant drugs which are rectally admininstered, from the rectalcompartment into the blood stream, is demonstrated with a microenematechnique. A male Sprague-Dawley rat weighing 225-250 g. is kept fastingfor 16 hours prior to the experiment which is conducted underpentabarbitol anesthesia. During the experiment, the rat is kept on a38° C. surface. The drug with adjuvant is administered rectally as a 0.3ml microenema using a 0.01 M phosphate buffer at a pH of 7.4 when thedepeptide is used as an adjuvant and at a pH of 4.5 when the metabolitesof epinephrine are used. Following administration of the drug solution,the rat anus is ligated with thread to avoid leakage of the solution.Blood samples are taken from the jugular vein at regular intervals andcentrifuged at 3000 rpm for 10 minutes to provide a plasma sample. Theamount of drug absorbed is analyzed as a function of time by appropriatemethods., e.g. by high-pressure liquid chromatography. The results ofthis method show that plasma levels for the various drugs increasedsignificantly after rectal administration in the presence of an adjuvantand relatively high levels were maintained for over 1.5 hours. Followingis a table of drug and adjuvant combinations which are evaluated inaccordance with the method described above:

    ______________________________________                                        Drug                 Adjuvant                                                 ______________________________________                                        1.   (6R-cis)-3-[ [(Aminocarbonyl)                                                                     Phenylalanyl-phenyl-                                      oxy]methyl]-7-methoxy-                                                                            alanine, 4-hydroxy-                                       8-oxo-7-[(2-thienylacetyl)                                                                        3-methoxymandelic                                         amino]-5-thia-1-azabicyclo                                                                        acid,                                                     [4.2.0]oct-2-ene-2- 3,4-dihydroxy-                                            carboxylic acid (cefoxitin);                                                                      mandelic acid                                        2.   Cefmetazole         phenylalanyl-phenyl-                                                          alanine,                                                                      4-hydroxy-3-methoxy-                                                          mandelic acid                                                                 3,4-dihydroxy-                                                                mandelic acid                                        3.   ampicillin          phenylalanyl-phenyl-                                                          alanine,                                                                      4-hydroxy-3-methoxy-                                                          mandelic acid,                                                                3,4-dihydroxy-                                                                mandelic acid                                        ______________________________________                                    

EXAMPLE XI

The ability of various of the adjuvants of the present invention toenhance the rate of absorption of significant drugs which are rectallyadministered, from the rectal compartment into the blood stream, isdemonstrated using suppository and microenema formulations. Twelve malebeagle dogs weighing 9.5-11 kg. are used and are fasted for 36 hoursprior to the experiment. The dogs are divided into three groups of fourand crossed over with respect to dosage form. Witepsol H-15 is used asan excipient to prepare with 8% gelatin in saline. Suppositories areadministered in the amount of 0.5 g. Mocroenemas are administered with avolume of 0.5 ml. The formulations may contain varying amounts ofadjuvant. Blood samples are taken at intervals from the external jugularvein. Blood samples are heparinized and centrifuged at 4000×G for 10minutes. The plasma levels of the drugs are analyzed as a function oftime using plasma aliquots for the assay of drug concentration. Theresults of this method show that the inclusion of adjuvant significantlyenhanced the bioavailability of the drugs in the blood stream. Followingis a table of drug and adjuvant combinations which are evaluated inaccordance with the method described above:

    ______________________________________                                        Drug                   Adjuvant                                               ______________________________________                                        1.     C.sub.16 H.sub.17 KN.sub.2 O.sub.4 S (penicillin                                                  Sodium 5-methoxy                                                              salicylate,                                                                   sodium salicylate                                  2.     amoxicillin         sodium 5-methoxy                                                              salicylate,                                                                   sodium salicylate                                  3.     (6R--cis)-3-[[Aminocarbonyl)                                                                      sodium 5-methoxy                                          oxy]methyl]-7-methoxy-8-                                                                          salicylate,                                               amino]-5-thia-1-azabicyclo                                                                        sodium salicylate                                         [4.2.0]oct-2-ene-2-                                                           carboxylic acid (cefoxitin)                                            ______________________________________                                    

EXAMPLE XII

The ability of various of the hydroxyaromatic acid adjuvants of thepresent invention to enhance the rate of absorption of insulin which isrectally administered from the rectal compartment into the blood stream,is demonstrated using a microenema technique. A male beagle dog weighing9.5 t 11 kg. is used. Rectal administration of insulin is in the form ofa 0.5 ml. or a 0.25 ml. microenema. Insulin microenema formulation aremade up in either 0.9% sodium chloride or in 0.9% sodium chloride with4% gelatin. Blood samples are taken at intervals for the externaljugular vein and treated with EDTA. Blood samples are centrifuged at4000×G for 10 minutes. Plasma glucose levels are determined at 650 nmusing the O-toluidine method. Plasma insulin levels are determined usingan immunospecific enzyme assay (Toyo Jozo Company, Ltd., Japan). Theresults of this method show that the presence of the adjuvant caused asignificant decrease in plasma glucose levels concommitant with a largeincrease in plasma insulin levels. Following is a table of drug andadjuvant combinations which are evaluated in accordance with the methoddescribed above:

    ______________________________________                                               Drug        Adjuvant                                                   ______________________________________                                        1.       cepheperin    Sodium 5-methoxy                                                              salicylate,                                                                   sodium salicylate                                      ______________________________________                                    

As already described, the methods of the present invention for enhancingthe rate of absorption of drugs from the rectal compartment are usefulfor a wide range of drugs. Without limiting the broad applicability ofthe novel methods, there are also pointed out a number of drugs forwhich the novel methods are particularly useful, thus comprisingpreferred embodiments of the present invention:

Cephanone

Cephaloridine

Ticaricillin

Cefmetazole;

Carbenicillin

Cefuroxine

(6R-cis)-3-[[(Aminocarbonyl)oxy]methyl]-7-methoxy]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (cefoxitin);

Cephaprin

C₁₆ H₁₇ KN₂ O₄ S (penicillin G);

Cefazolin

EXAMPLE XIII Preparation of Sodium 2-hydroxy-5-methoxy benzenesulfonate

p-Methoxyphenol (12.4 g) was dissolved in chloroform (100 ml) and cooledin ice. Chlorosulfonic acid (11.6 g) was added dropwise to the stirredreaction mixture. The cooling bath was removed after the addition andstirring continued for 24 hours at room temperature. The chloroform wasthen evaporated off and the residue was vacuum dried to a hygroscopiclight brown solid weighing 20.5 g which was2-hydroxy-5-methoxy-benzenesulfonic acid.

NMR (CDCl₃) and 3.73 (3H, s, OCH₃), 6.8-7.2 (3H, m, aromatic H), and9.86 (2H, broad s, OH and SO₃ H). IR (film) 3500-2900, 1512, 1470, 1229,1198, 996, 938 cm⁻¹.

The above sulfonic acid (10 g) was dissolved in water (10 ml) and pouredinto 75 ml of saturated sodium chloride solution. A white solidseparated immediately. It was filtered and dried. Crystallization fromwater gave the pure sodium salt of 2-hydroxy-5-methoxybenzenesulfonicacid (6.6 g).

NMR (D₂ O) and 3.83 (3H, s, OCH₃), 7.05 and 7.33 (3H, multiplets,aromatic). IR (KBr) 3260, 1518, 1440, 1300, 1280, 1240, 1210, 1905, 1045cm⁻¹.

While in the foregoing there has been provided a detailed description ofparticular embodiments of the present invention, it is to be understoodthat all equivalents obvious to those having skill in the art are to beincluded within the scope of the invention as claimed.

What we claim and desire to secure by Letters Patent is:
 1. A method for enhancing the rate of absorption of a rectally administered β-lactam antibiotic drug from a rectal compartment into the blood stream, said method comprising the steps of preparing a β-lactam drug form capable of being rectally administered, said drug form comprising a therapeutically effective dosage amount of a drug selected from the group consisting of a thienamycin, penicillin or cephalosporin capable of being absorbed into the blood stream from the rectal compartment and an adjuvant of the formula: ##STR8## wherein R₁ is CO₂ H, (CH₂)COOH, ##STR9## SO₃ H, or a pharmaceutically acceptable salt thereof wherein R₂ is OH, H, a lower alkoxy radical, a lower alkyl radical, a halo radical, or a tri-halo lower alkyl radical, and wherein y is an integer of 1 or 2, said adjuvant being present in said drug form in a sufficient amount to be effective in enhancing said absorption rate, and administering said drug form into said rectal compartment.
 2. The method of claim 1 wherein said drug is selected from the group consisting of penicillin G., ampicillin, amoxicillin, methacillin, carbenicillin, cefoxitin, cephamandole, cephmetazole, cephanone, oxacephalosporin, or N-formimidoyl thienamycin.
 3. The method of claim 1 wherein said drug comprises cefoxitin.
 4. The method of claim 1 wherein said adjuvant is 5-methoxysalicylic acid, salicylic acid, homovanillic acid; 2,5-dihydroxybenzoic acid; 2,4-dihydroxybenzoic acid; 5-methoxy-2-hydroxyphenylsulfonic acid; 3-methylsalicylic acid; 5-methylsalicylic acid; 5-tert-octylsalicylic acid; 3-tert-butyl-6-methylsalicylic acid; 3,5-diisopropylsalicylic acid; 3-tert-butyl-5-methylsalicylic acid; guaicolsulfonic acid; 5-bromosalicylic acid; 3,5-dibroamosalicylic acid; 5-iodosalicylic acid; 3,5-diiodosalicylic acid; 3,5-diiodosalicylic aci; 2-hydroxyphenylacetic acid; 2-hydroxyphenylmethanesulfonic acid; 5-trifluoromethyl-2-hydroxybenzoic acid; 3-methoxysalicylic acid; 5-octyloxysalicylic acid; 5-butoxysalicylic acid; 5-chlorosalicylic acid; 2-hydroxy-3-methoxy-benzoic acid; or the sodium salts thereof.
 5. The method of claim 1 wherein said adjuvant is 5-methoxysalicylic acid, or homovanillic acid and the sodium salts thereof.
 6. The method of claim 1 wherein the adjuvant is salicylic acid or sodium salicylate.
 7. The method of claim 1 wherein said administering step is carried out at a pH of below 5.5 or above 7.5.
 8. The method of claim 1 wherein said drug form is a suppository.
 9. The method of claim 1 wherein said suppository comprises a soft elastic gelatin capsule containing said drug and said adjuvant.
 10. The method of claim 1 wherein said administering step is accomplished by a microenema.
 11. A rectally administered drug form comprising a therapeutically effective dosage amount of a drug selected from the group consisting of a thienamycin, penicillin or cephalosporin capable of being absorbed into the blood stream from a rectal compartment and an adjuvant ##STR10## wherein R₁ is CO₂ H, (CH₂)COOH, ##STR11## SO₃ H, or a pharmaceutically acceptable salt thereof wherein R₂ is OH, H, a lower alkoxy radical, a lower alkyl radical, a halo radical, or a tri-halo lower alkyl radical, and wherein y is an integer of 1 or 2, said adjuvant being present in said drug form in a sufficient amount to be effective in enhancing the absorption rate of said drug from from said rectal compartment into the bloodstream.
 12. The drug form of claim 11 wherein said drug is selected from the group consisting of penicillin G., ampicillin, amoxicillin, methacillin, carbenicillin, cefoxitin, cephamandole cephaprin, cephmetazole, cephanone, oxacephalosporin, or N-formidoyl thienamycin.
 13. The drug form of claim 11 wherein said drug comprises cefoxitin.
 14. The drug form of claim 11 wherein said adjuvant is 5-methoxysalicylic acid, salicylic acid, homovanillic acid; 2,5-dihydroxybenzoic acid; 2,4-dihydroxybenzoic acid; 5-methoxy-2-hydroxyphenylsulfonic acid; 3-methylsalicylic acid; 5-methylsalicylic acid; 5-tert-octylsalicylic acid; 3-tert-butyl-6-methylsalicylic acid; 3,5-diisopropylsalicylic acid; 3-tert-butyl-5-methylsalicylic acid; guaicolsulfonic acid; 5-bromosalicylic acid; 3,5-dibroamosalicylic acid; 5-iodosalicylic acid; 3,5-diiodosalicylic acid; 3,5-diiodosalicylic acid; 2-hydroxyphenylacetic acid; 2-hydroxyphenylmethanesulfonic acid; 5-trifluoro-methyl-2-hydroxybenzoic acid; 3-methoxy-salicylic acid; 5-octyloxysalicylic acid; 5-butoxy-salicylic acid; 3,4-dihydroxyphenylacetic acid; 5-chlorosalicylic acid; 2-hydroxy-3-methoxybenzoic acid; salicyluric acid; or the sodium salts thereof.
 15. The drug form of claim 11 wherein said adjuvant is 5-methoxysalicylic acid, or homovanillic acid, and the sodium salts thereof.
 16. The drug form of claim 11 wherein the adjuvant is salicylic acid or sodium salicylate.
 17. The drug form of claim 11 wherein said administering step is carried out at a pH of below 5.5 or above 7.5.
 18. The drug form of claim 11 wherein said drug form is a suppository.
 19. The drug form of claim 18 wherein said suppository comprises a soft elastic gelatin capsule containing said drug and said adjuvant. 